免疫球蛋白G4检测在不明原因肝损伤诊断中的应用价值

Application value of immunogiobulin G4 detection in unexplained liver injuries

目的探讨既往诊断为不明原因肝损伤患者免疫球蛋白G4（IgG4）浆细胞的表达水平，评价其是否可重新诊断为IgG4相关性疾病（IgG4-RD），并分析肝组织存在IgG4阳性浆细胞浸润但未达到IgG4-RD诊断标准患者的临床特征。方法纳入2010年8月至2016年7月行肝穿刺检查后仍不能明确肝损伤病因的患者33例。应用免疫组织化学法对肝组织行IgG、IgG4染色，分析患者是否符合IgG4-RD的诊断标准，以及肝组织IgG4阳性浆细胞浸润与血清学指标（ALT、AST、ALP、GGT、IgG）、肝组织炎症分级和纤维化分期的关系。统计学方法采用卡方检验、Fisher确切概率法、t检验和Wileoxon秩和检验。结果33例不明原因肝损伤患者的平均发病年龄为（50．48±14．52）岁，有10例（30．3％）患者肝脏中存在不同程度的IgG4阳性浆细胞浸润，其中1例患者肝脏中IgG4阳性浆细胞个数〉10个／高倍镜视野（HPF），IgG4／IgG〉40％，伴有血清IgG4升高和肝左叶外侧端小圆形低密度结节，可重新诊断为IgG4-RD。该例患者肝功能相关指标ALT为948U／L，AST为658U／L，ALP为176u／L，GGT为197U／L，TBil为21．5gmol／L，DBil为10．0μmol／L。根据肝组织中是否存在IgG4阳性浆细胞浸润，将33例患者分为有IgG4阳性浆细胞浸润组（IgG4阳性组）10例和无Ig04阳性浆细胞浸润组（IgG4阴性组）23例。kG4阳性组和Ig64阴性组患者AIJ、AST、ALP、GGT的中位水平（分别为26．0U／L比31．0u／L，28．5U／L比32．0U／L，114．0U／L比77．0U／L，65．0U／L比36．0U／L）比较差异均无统计学意义（Z=-0．098、-0．216、-0．862、-0．705，P均〉0．05）；IgG4阳性组患者中位血清IgG水平高于IgG4阴性组（17．15g／L比13．65g／L），差异有统计学意义（Z=-1．776，P=0．035）。结论IgG4-RD可能是肝损伤的病因。伴或不伴IgG4阳性浆细胞浸润的患者，其临床特征、血清学指标和肝脏炎性反应程度无明显差异。

Objective To investigate the expression level of immunoglobulin G （IgG）4 cells in patients previously diagnosed as unexplained liver injuries, and to analyze whether these patients could be diagnosed as immunoglobulin G4-related disease （IgG4-RD）. The clinical characteristics of patients with IgG4 positive cells infiltration in liver tissues who did not met IgG4-RD diagnosis criteria were also analyzed. Methods From August 2010 to July 2016, 33 patients with unexplained liver injuries even after liver biopsy were enrolled. Immunostaining of IgG and IgG4 in liver tissue slices was performed. Whether the patients met the IgG4-RD diagnosis criteria was analyzed. Also, the relation between IgG4 positive cell infiltration in liver tissues and serum parameters （alanine aminotransferase （ALT）, aspartate transaminase （ AST）, alkaline phosphatase （ALP）, y-glutamyl transpeptadase （GGT）, IgG）, the classification of liver inflammation and stage of liver fibrosis were analyzed. Chi-square, Fisher exact probability method, t test and Wilcoxon rank and inspection were used for statistical analysis. Results Among 33 patients with unexplained liver injuries, average age of onset of the disease was （50.48±14.52） years old. Ten patients （30.3 %） presented with different degree of IgG4 positive cells infiltration in liver. In one patient, the IgG4 positive cell number in liver tissue was over 10/high-powered field （HPF）, IgG4＋/ IgG＋ ratio was over 40%, the serum IgG4 increased and low density nodules in the left hepatic lobe level, which met the diagnostic criteria of IgG4-RD. Serum parameters of liver function of this patient were as follows, ALT 948 U/L, AST 658 U/L, ALP 176 U/L, GGT 197 U/L; TBil 21.5 pamol/L, DBil 10. 0 μmol/L. According to whether there were IgG4 positive cells infiltration in liver tissues, 33 patients were divided into IgG4 positive cells infiltration group （IgG4 positive group, 10 cases） and no IgG4 positive cells infiltration group （IgG4 negative group, 23 cases）. The medium levels of ALT, AST, ALP and GGT in the IgG4 positive group and the IgG4 negative group were 26.0 U/L vs 31.0 U/L, 28.5 U/L vs 32.0 U/L, 114.0 U/L vs 77.0 U/L, 65.0 U/L vs 36.0 U/L, respectively and there were no statistically significant differences （Z=-0. 098, -0. 216, -0. 862, -0. 705% all P〈0. 05）. The serum IgG level of the IgG4 positive group was higher than that of the IgG4 negative group （17. 15 g/L vs 13. 65 g/L）, and the difference was statistically significant （Z =- 1. 776, P = 0. 035）. Conclusions IgG4-RD may he the reason of liver injury. There are no significant differences in clinical charateristies, serum parameters and inflammation degree in liver tissue between patients with or without IgG4 positive cells infiltration.